Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study.

Abstract

BACKGROUND:

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children.

METHODS:

Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose.

RESULTS:

Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles.

CONCLUSIONS:

This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

• Authors: Rishi R Lulla, Stewart Goldman, Tohru Yamada, Craig W Beattie, Linda Bressler, Michael Pacini, Ian F Pollack, Paul Graham Fisher, Roger J Packer, Ira J Dunkel, Girish Dhall, Shengjie Wu, Arzu Onar, James M Boyett, Maryam Fouladi
• Journal: Neuro-oncology (Neuro Oncol) Vol. 18 Issue 9 Pg. 1319-25 (09 2016) ISSN: 1523-5866 [Electronic] England
• PMID: 27022131 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Peptide Fragments
• Tumor Suppressor Protein p53
• Azurin
• azurin (50-77)

Topics

• Adolescent
• Adult
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Azurin (pharmacokinetics, therapeutic use)
• Central Nervous System Neoplasms (drug therapy, metabolism, pathology)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Male
• Maximum Tolerated Dose
• Neoplasm Recurrence, Local (drug therapy, metabolism, pathology)
• Neoplasm Staging
• Peptide Fragments (pharmacokinetics, therapeutic use)
• Prognosis
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination (drug effects)
• Young Adult